BACKGROUND:Therapeutic strategies that induce effective neuroprotection and enhance intrinsic repair mechanisms are central goals for future treatment of multiple sclerosis (MS), as well as other diseases. Laquinimod (LQ) is an orally administered, central nervous system (CNS)-active immunomodulator with demonstrated efficacy in MS clinical trials and a favorable safety and tolerability profile.AIMS: We aimed to explore the pathological, functional, and behavioral consequences of prophylactic and therapeutic (after presentation of peak clinical disease) LQ treatment in the chronic experimental autoimmune encephalomyelitis (EAE) mouse model of MS.MATERIALS AND METHODS:Active EAE-induced 8-week-old C57BL/6 mice were treated with 5 or 25 mg/kg/day LQ via oral gavage beginning on EAE post-immunization day 0, 8, or 21. Clinical scores and rotorod motor performance were assessed throughout the disease course. Immune analysis of autoantigen-stimulated splenocytes, electrophysiological conduction of callosal axons, and immunohistochemistry of white matter-rich corpus callosum and spinal cord were performed.RESULTS:Prophylactic and therapeutic treatment with LQ significantly decreased mean clinical disease scores, inhibited Th1 cytokine production, and decreased the CNS inflammatory response. LQ-induced improvement in axon myelination and integrity during EAE was functional, as evidenced by significant recovery of callosal axon conduction and axon refractoriness and pronounced improvement in rotorod motor performance. These improvements correlate with LQ-induced attenuation of EAE-induced demyelination and axon damage, and improved myelinated axon numbers.DISCUSSION:Even when initiated at peak disease, LQ treatment has beneficial effects within the chronic EAE mouse model. In addition to its immunomodulatory effects, the positive effects of LQ treatment on oligodendrocyte numbers and myelin density are indicative of significant, functional neuroprotective and neurorestorative effects.CONCLUSIONS: Our results support a potential neuroprotective, in addition to immunomodulatory, effect of LQ treatment in inhibiting ongoing MS/EAE disease progression.

Lacquinimod is not a very good DMT based on the doses used in MS and was worse than the interferons at stopping relapses in MS, yet in EAE it could stop CNS autoimmunity and not surprisingly this was associated with inhibition in the development of autoimmunity in the CNS and so this will inhibit the downstream consequences of this like CNS infiltration and the damage that this causes like axonal damage and myelin damage.

In this study it is claimed that there is neurorestorative function which sounds promising. However, was this “improvement” and “recovery” in nerve function or more likely “slowing of the loss of function” so if the drug has a peripheral immunosuppressive action the downstream consequences will not occur. This is very different from having function shown to be lost and then actually recovering the lost function. In one scenario there is recovery from something in the other the something never happens. Based on the data it can be largely explained by immunosuppression.

The EAE brigade has built the picture that MS is a T cell mediated disease but this has not been compellingly shown and then we have the bombshell that anti-CD20 B cell therapy appears to block relapsing MS. So how does this happen,it is because T cells express CD20 and this subset of cells cause MS,is it because B cells act as antigen presenting cells or is it because B cells contain the aetiological factor such as EBV and so getting rid of them blocks the trigger. This study argues that B cells are involved in antigen presentation as the authors and others have suggested in the past.

Antigen presentation to CD4 cells requires MHC class II and in this study they stopped B cells producing MHC class II and they did not get EAE, suggesting that B cells are active as antigen presenting cells and EAE could develop in the abense of an anti-myelin antibody response, but I guess we knew this already from many previous studies, including the finding that EAE can develop in B cell deficient mice.

Backgound: Multiple Sclerosis has two clinical phases reflecting distinct but inter-related pathological processes: focal inflammation drives the relapse-remitting stage and neurodegeneration represents the principal substrate of secondary progression. In contrast to the increasing number of effective anti-inflammatory disease modifying treatments for relapse-remitting disease, the absence of therapies for progressive disease represents a major unmet clinical need. This raises the unanswered question of whether elimination of clinical relapses will prevent subsequent progression and if so how early in the disease course should treatment be initiated. Experimental autoimmune encephalomyelitis in the Biozzi ABH mouse recapitulates the clinical and pathological features of multiple sclerosis including relapse-remitting episodes with inflammatory mediated demyelination and progressive disability with neurodegeneration. To address the relationship between inflammation and neurodegeneration we used an auto-immune tolerance strategy to eliminate clinical relapses in EAE in a manner analogous to the clinical effect of disease modifying treatments.

RESULTS:By arresting clinical relapses in EAE at two distinct stages, early and late disease, we demonstrate that halting immune driven demyelination even after the first major clinical event is insufficient to prevent long-term neurodegeneration and associated gliosis. Nonetheless, early intervention is partially neuroprotective, whereas later interventions are not. Furthermore early tolerisation is also associated with increased remyelination.

CONCLUSIONS:These findings are consistent with both a partial uncoupling of inflammation and neurodegeneration and that the regenerative response of remyelination is negatively correlated with inflammation. These findings strongly support the need for early combinatorial treatment of immunomodulatory therapies and neuroprotective treatments to prevent long-term neurodegeneration in multiple sclerosis

We have been talking about the best treatment for stopping relapsing disease in animals over the past couple of weeks. This is a transient depletion followed by delivery of the disease causing molecules via an immune tolerogenic route. In this study relapsing neurodegenerative disease was set in motion and then at different time points further relapses were stopped. We then looked to see what had happened in the CNS a few months later. It was clear that despite elimination of relapsing disease some nerve tracts showed progressive neurodegeneration, rather disturbing this occurred even after after a single attack. With each attack different nerve tracts started to degenerate. Therefore even in this simple model of MS it can be seen that relapses cause nerve damage and therefore stopping them, as quickly as possible, is important. Likewise in this case the autoimmune response can trigger a neurodegenerative condition and this progressive neurodegeneration can occur even from disease onset. From a clinical prospective stopping the disease in its tracks early was not associated with marked clinical progression but this could be seen once a number of relapses had occurred. This study further suggests that we should aim to treat early and effectively and to us it suggests that targeting T cells, at least in the periphery will not be the answer to treating progressive MS. This is not something that T cell immunologists/EAEologists are willing to accept or read. Can the odd autoreactive T cell be found in the peripheral blood and/or CNS, yes sure they can be. The immune tolerance needs autoreactive T cells to be present fr it to work. So this allows the doubters to cling to their increasingly flimsy view of T cells causing progressive MS. Yet Neuros continue to try and stop progressive MS by targeting T cell responses. So far targeting these cells in the periphery has uniformly failed to stop progressive MS.

At what point do you stop and say that some bits of autoimmune dogma are probably not correct

BACKGROUND:Multiple sclerosis (MS) and epilepsy are both fairly common and it follows that they may sometimes occur together in the same people by chance. We sought to determine whether hospitalisation for MS and hospitalisation for epilepsy occur together more often than expected by chance alone.

METHODS:We analysed two datasets of linked statistical hospital admission records covering the Oxford Record Linkage Study area (ORLS, 1963-1998) and all England (1999-2011). In each, we calculated the rate of occurrence of hospital admission for epilepsy in people after admission for MS, compared with equivalent rates in a control cohort, and expressed the results as a relative risk (RR).

RESULTS:The RR for hospital admission for epilepsy following an admission for MS was significantly high at 4.1 (95% confidence interval 3.1-5.3) in the ORLS and 3.3 (95% CI 3.1-3.4) in the all-England cohort. The RR for a first recorded admission for epilepsy 10 years and more after first recorded admission for MS was 4.7 (2.8-7.3) in ORLS and 3.9 (3.1-4.9) in the national cohort. The RR for the converse-MS following hospitalisation for epilepsy-was 2.5 (95% CI 1.7-3.5) in the ORLS and 1.9 (95% CI 1.8-2.1) in the English dataset.

CONCLUSIONS: MS and epilepsy occur together more commonly than by chance. One possible explanation is that an MS lesion acts as a focus of an epileptic seizure; but other possibilities are discussed. Clinicians should be aware of the risk of epilepsy in people with MS. The findings may also suggest clues for researchers in developing hypotheses about underlying mechanisms for the two conditions.

We have been talking about whether epilepsy drugs are useful for progression in MS. There was a bit of a heated debate when it was said there wasn’t based on analysis of historical medical records of MSers on anti-epileptic drugs and ProfG’s response indicating that this type of analysis was not sufficient to make any conclusions. However this study suggests that epilepsy can occur as a result of MS and this why one could look for historical data.

OBJECTIVE:We have previously shown that autoimmunity following alemtuzumab treatment of multiple sclerosis can be predicted by high baseline serum interleukin IL-21 (IL-21), as measured using a now 'redundant' enzyme linked immunosorbent assay (ELISA). Here we ask whether currently available ELISAs have similar prognostic value.DESIGN:Serum IL-21 from 141 individuals with relapsing remitting multiple sclerosis was measured using the now 'redundant' IL-21 ELISA and five further currently available kits. All patients had been treated with alemtuzumab; 61/141 had developed secondary autoimmunity.RESULTS:The 'redundant kit', and one current kit, confirmed higher baseline serum IL-21 in patients with autoimmunity (542 pg/mL vs. 222 pg/mL and 53.1 pg/mL vs. 9.3 pg/mL respectively) and showed positive correlation. However, only the 'redundant' kit had predictive utility.CONCLUSIONS: Currently available IL-21 ELISA kits should not be used to counsel individuals with multiple sclerosis considering treatment with alemtuzumab.

An ELISA that detected soluble interleukin 21 was used and was suggested to predict, in part, whether autoimmunity may develop after alemtuzumab treatment. An ELISA against interleukin 21 is may contain a capture IL-21 antibody that is stuck to plastic and a detect anti-body that has a dye attached to it. So you add blood which contains IL-21 that is bound to the capture antibody and then you add the detect antibody that can now bind to the captured IL-21 and the more IL-21 in the blood the more that is captured the more detection signal you get. You then take a known amount of IL-21 and put this in the assay and then you can work out how much is in the blood. You can make these ELISAs up or eventually a company will make a kit, which is easier to do and generally gives more consistent results. This study tests a few commercial kits and none of them performed as well as the original ELISA and they had n predictive value. There are clearly problems with the ELISAs as they are not accurately detecting the levels in the blood ~500pg/ml in one verses 50pg/ml. This paper says that you can't use current commercial kits to predict whether you will get autoimmunity after campath. Was the original interpretation correct.

OBJECTIVE Chronic cerebrospinal venous insufficiency (CCSVI) is a condition associated with multiple sclerosis (MS) and manifested by stenoses in the extracranial venous circulation. There is a need for an objective non-invasive assessment of CCSVI that is able to accurately identify the location of stenoses and quantify physiological changes in blood flows following treatment.

METHOD:A duplex ultrasound method, extracranial duplex ultrasound (ECDU), is described where the internal jugular veins (IJVs) and vertebral veins (VVs) were examined in the supine and sitting position before and after venoplasty in eight patients with clinically diagnosed MS. High-resolution B-mode imaging was used to detect obvious stenoses, intra-luminal membranes, valve abnormalities and vein wall thickening. ECDU was then used to assess blood flow including reflux. To assess obstruction, venous blood volume flows (BVFs) were taken bilaterally from the proximal (J1), mid (J2) and distal (J3) segments of the IJVs and the mid cervical VVs. To assess cerebral perfusion, bilateral BVF measurements were taken, in the supine position only, from the proximal internal carotid arteries (ICA) and mid cervical vertebral arteries (VA). The global arterial cerebral blood flow (GACBF) was then calculated as the sum of the ICA and VA measurements.

RESULTS: Pre-venography ECDU detected IJV stenoses or obstruction in all patients. Venography findings were consistent with those of the pre-treatment ECDU with the exception of the detection of bilateral IJV stenoses in two patients diagnosed with unilateral IJV stenosis by ECDU. A significant improvement in GACBF was evident following venoplasty (p < 0.05). A trend to improvement in the post-treatment BVFs of both the IJVs and the mid cervical VVs was also observed. This improvement was most marked in the left VVs (p = 0.052) and the J2 segment of right IJVs (p < 0.05).

CONCLUSION: The ECDU examination described provides a reliable objective assessment of IJV and VV stenoses and, with the use of BVFs, can quantify the degree of obstruction. These results support the use of ECDU as a non-invasive post-operative assessment of the success of venoplasty. The ability of ECDU to measure GACBF provides an additional parameter to monitor vascular pathophysiology in MS patients. The current findings support the view that the early symptomatic benefits observed after venoplasty for stenoses in the extracranial venous circulation may be the result of increased cerebral perfusion.

Taking a step back to look at the overall picture, I believe 2013 has been on balance a negative year in this aspect.

It is clear that the 100% concordance of CCSVI with MS is an unsustainable view. However the criteria applied to detect CCSVI does seem to occur in more MSers than Non-MSers, although some studies find it a vanishingly rare occurrence.

However, it is also the case that CCSVI criteria occurs in non- MSers. CCSVI criteria are more common in older MSers and so it is perhaps consequential and not causal. Therefore the causal link is clearly wrong. Those in support argue that the techniques used that do not show CCSVI are not fit for purpose, but one should argue that the goal posts are being shifted when the hurdle is being not being cleared.

More problematical is that the CCSVI diagnostic criteria are not stable over time and therefore there is clear problem in any clinicial study on this subject. A trial by CCSVI protagonists was stopped because of apparent worsening and whilst other unblinded studies suggest some perceived benefit, it was evident that this was typically short lasting, for a few months. Therefore the chances of success of long term trials lasting years are minimal,

Personally I hope the ongoing trials actually show some benefit, but taking a more dispassionate view I am not expecting this. This whole saga has elements that have reverberated and repeated in MS history....what will be the next treatment option that you can bypass the established medical profession. Hopefully 2014 will bring even more clarity on this issue.

Friday, 27 December 2013

Objectives: Determine the likelihood of worsening clinical status in the near-term course of progressive MS and evaluate the predictive validity of our diagnostic impression of progressive forms of MS.Methods:Retrospective review of charts from 175 patients seen between 2000 and 2007 who were diagnosed with either primary or secondary progressive multiple sclerosis. Data extracted included demographic factors, neurological examination findings to determine EDSS, timed 25 foot walk (T25FW) when available, duration of symptoms, clinical course as documented on initial visit, and history of disease-modifying agent (DMA) use. Significant change in EDSS was defined as a change of one point or more from initial to final clinical evaluation. Significant change in T25FW was defined as a ±20% difference from baseline.Results:Of the 175 charts reviewed, 35 patients met criteria and had sufficient documentation to allow for EDSS abstraction. Twenty-four patients (68.6%) showed no significant change in EDSS from baseline while eleven patients (31.4%) worsened and none improved. For those patients that had T25FW data available, 6 out of 20 (30%) patients worsened while 11 (55%) showed no change. Three patients (15%) improved.Conclusion:In this observational study at a tertiary care MS centre, patients classified as progressive MS did not progress as often, or as rapidly, as previous studies have suggested. Greater than two-thirds of patients in this cohort, did not increase 1 step on the EDSS.About 70% of progressive MSers did not progress within the observation period in EDSS and for walking it was 55% . The cupid trial had problems because progressive Msers did better than predicted. I wonder if this relates to being in an age of DMT that slows damage accumulation and maybe healthier life styles. Who knows?

Multiple sclerosis (MS) is a complex multifactorial disease of the central nervous system (CNS) for which animal models have mainly addressed downstream immunopathology but not potential inducers of autoimmunity. In the absence of a pathogen known to cause neuroinflammation in MS, Mycobacterial lysate is commonly used in the form of complete Freund's adjuvant to induce autoimmunity to myelin proteins in Experimental Allergic Encephalomyelitis (EAE), an animal model for MS. The present study demonstrates that a protein from the human endogenous retrovirus HERV-W family (MSRV-Env) can be used instead of mycobacterial lysate to induce autoimmunity and EAE in mice injected with MOG, with typical anti-myelin response and CNS lesions normally seen in this model. MSRV-Env was shown to induce proinflammatory response in human macrophage cells through TLR4 activation pathway. The present results demonstrate a similar activation of mouse dendritic cells and show the ability of MSRV-Env to trigger EAE in mice. In previous studies, MSRV-Env protein was reproducibly detected in MS brain lesions within microglia and perivascular macrophages. The present results are therefore likely to provide a model for MS, in which the upstream adjuvant triggering neuroinflammation is the one detected in MS active lesions. This model now allows pre-clinical studies with therapeutic agents targeting this endogenous retroviral protein in MS.

In rats and marmoset, EAE can be induced in animals using myelin antigen in Freund's incomplete adjuvant (something that promotes immune response generation) which is Freunds complete adjuvant without the mycobacteria. In this study they put a component of human endogenous retrovirus in the adjuvant with myelin and EAE developed. They suggest that this will give them a model to study the role of targeting retrovirus. This may be the case but studies of anti-HERV are in advanced development as is the Charcot project so is it past the point of animal studies.

During multiple sclerosis (MS), the main axon cystoskeleton proteins, neurofilaments (NF), are altered, and their release into the cerebrospinal fluid correlates with disease severity. The role of NF in the extraaxonal location is unknown. Therefore, we tested whether synthetic peptides corresponding to the tubulin-binding site (TBS) sequence identified on light NF chain (NFL-TBS.40-63) and keratin (KER-TBS.1-24), which could be released during MS, modulate remyelination in vitro. Biotinylated NFL-TBS.40-63, NFL-Scramble2, and KER-TBS.1-54 (1-100 μM, 24 hr) were added to rat oligodendrocyte (OL) and astrocyte (AS) cultures, grown in chemically defined medium. Proliferation and differentiation were characterized by using specific antibodies (A2B5, CNP, MBP, GFAP) and compared with untreated cultures. Lysophosphatidyl choline (LPC; 2 × 10(-5) M) was used to induce OL death and to test the effects of TBS peptides under these conditions. NFL-TBS.40-63 significantly increased OL differentiation and maturation, with more CNP(+) and MBP(+) cells characterized by numerous ramified processes, along with myelin balls. When OL were challenged with LPC, concomitant treatment with NFL-TBS.40-63 rescued more than 50% of OL compared with cultures treated with LPC only. Proliferation of OL progenitors was not affected, nor were AS proliferation and differentiation. NFL-TBS.40-63 peptide induces specific effects in vitro, increasing OL differentiation and maturation without altering AS fate. In addition, it partially protects OL from demyelinating injury. Thus release of NFL-TBS.40-63 caused by axonal damage in vivo could improve repair through increased OL differentiation, which is a prerequisite for remyelination.

Neurofilament is a protein within nerves and this gets released when they are damaged. Fragments of this molecule were shown to promote oligodendrocyte activity and so as a consequence of damage to nerves repair is stimulated

Objective. Chronic inflammatory demyelinating polyneuropathy (CIDP) has been reported in patients with multiple sclerosis (MS). However, there have been limited reports of peripheral neuropathy as a complication of neuromyelitis optica (NMO). In this paper, we showed the characteristics and differences between peripheral neuropathy as a complication of MS and NMO. Method. We analyzed a series of 58 MS and 28 NMO patients and evaluated nerve conduction studies (NCS) in 21 MS and 5 NMO patients. Results. Six of the 58 MS and 3 of the 28 NMO patients revealed abnormal NCS findings. Three (5.2%) of the 58 MS patients fulfilled the criteria for CIDP. One (3.6%) of the 28 NMO patients showed peripheral neuropathy at the same time of NMO relapse, although CIDP was not seen in NMO. The other 5 (3 MS and 2 NMO) patients were complicated with neuropathy caused by concomitant diabetes mellitus and Sjögren's syndrome. Conclusion. Frequency of abnormal NCS findings might exhibit no significant difference between MS and NMO, although the cause and pathophysiology of peripheral neuropathy were different in MS and in NMO. There might be a group of NMO who were affected simultaneously in the central and peripheral nervous tissues.

For many we are lead to believe
that MS is a CNS disease, here it shows that there can be peripheral nerve abnormalities. Is this a consequence of CNS problems or a primary issue. Some of the antigens in the CNS are present in the Peripheral nervous system also e.g. myelin basic protein and myelin associated glycoprotein. In EAE in rabbit there can be quite a lot of peripheral nerve involvement. Whilst a minor component in MS, peripheral nerve issues needs to be built into the big picture.

Wednesday, 25 December 2013

OBJECTIVE:To review the beneficial and harmful effects of laughter.DATA SOURCES AND REVIEW METHODS:We searched Medline (1946 to June 2013) and Embase (1974 to June 2013) for reports of benefits or harms from laughter in humans, and counted the number of papers in each category.RESULTS:Benefits of laughter include reduced anger, anxiety, depression, and stress; reduced tension (psychological and cardiovascular); increased pain threshold; reduced risk of myocardial infarction (presumably requiring hearty laughter); improved lung function; increased energy expenditure; and reduced blood glucose concentration. However, laughter is no joke-dangers include syncope, cardiac and oesophageal rupture, and protrusion of abdominal hernias (from side splitting laughter or laughing fit to burst), asthma attacks, interlobular emphysema, cataplexy, headaches, jaw dislocation, and stress incontinence (from laughing like a drain). Infectious laughter can disseminate real infection, which is potentially preventable by laughing up your sleeve. As a side effect of our search for side effects, we also list pathological causes of laughter, among them epilepsy (gelastic seizures), cerebral tumours, Angelman's syndrome, strokes, multiple sclerosis, and amyotrophic lateral sclerosis or motor neuron disease.CONCLUSIONS: Laughter is not purely beneficial. The harms it can cause are immediate and dose related, the risks being highest for Homeric (uncontrollable) laughter. The benefit-harm balance is probably favourable. It remains to be seen whether sick jokes make you ill or jokes in bad taste cause dysgeusia, and whether our views on comedians stand up to further scrutiny

BACKGROUND:Modifiable lifestyle factors represent important targets for preventive intervention in multiple sclerosis (MS). We aimed to explore the association of cigarette smoking and alcohol consumption with major MS morbidity outcomes.METHODS: We surveyed a large, international sample of people with MS recruited via Web 2.0 platforms about type of MS, relapse rates, disability, disease activity, health-related quality of life (HRQOL), alcohol use and smoking.RESULTS: Of 2469 respondents with confirmed MS, 11.7% were current and 40.3% former smokers. Most (61.5%) consumed less than 15g alcohol weekly; few (0.8%) drank large amounts. Moderate alcohol consumption was associated with increased HRQOL; and after controlling for age and gender, was associated with lower odds of significant disability (41% decrease). After controlling for age, gender and alcohol use, smokers had an increased likelihood of major mobility requirements by 90% compared to never smokers. There was no association between alcohol or smoking and relapse rate or disease activity after controlling for age and gender, however among former smokers, a longer duration of smoking cessation was associated with reduced disease activity. Smokers had significantly lower HRQOL than never smokers and former smokers; heavier smoking was associated with greater decreases in HRQOL.CONCLUSION: This cross-sectional study supports previous research showing a link between morbidity indicators in MS and alcohol use and smoking. While people with MS should be advised of the potential risks of smoking, any risks and benefits of alcohol consumption require validation using a prospective cohort of people with MS.

CB2, the cannabinoid receptor expressed primarily on hematopoietic cells and activated microglia, mediates the immunoregulatory functions of cannabinoids. The involvement of CB2 in EAE has been demonstrated by using both endogenous and exogenous ligands. We showed previously that CB2 selective agonists inhibit leukocyte rolling and adhesion to CNS microvasculature and ameliorate clinical symptom in both chronic and remitting-relapsing EAE models. Here we showed that Gp1a, a highly selective CB2 agonist, with a four log higher affinity for CB2 than CB1, reduced clinical scores and facilitated recovery in EAE in conjunction with long term reduction in demyelination and axonal loss. We also established that Gp1a affected EAE through at least two different mechanisms, i.e. an early effect on Th1/Th17 differentiation in peripheral immune organs, and a later effect on the accumulation of pathogenic immune cells in the CNS, associated with reductions in the expression of CNS and T cell chemokine receptors, chemokines and adhesion molecules. This is the first report on the in vivo CB2-mediated Gp1a inhibition of Th17/Th1 differentiation. We also confirmed the Gp1a-induced inhibition of Th17/Th1 differentiation in vitro, both in non-polarizing and polarizing conditions. The CB2-induced inhibition of Th17 differentiation is highly relevant in view of recent studies emphasizing the importance of pathogenic self-reactive Th17 cells in EAE/MS. In addition, the combined effect on Th17 differentiation and immune cell accumulation into the CNS, emphasize the relevance of CB2 selective ligands as potential therapeutic agents in neuroinflammation.

Neuroplasticity is essential to prevent clinical worsening despite continuing neuronal loss in several brain diseases, including multiple sclerosis (MS). The precise nature of the adaptation mechanisms taking place in MS brains, ensuring protection from disability appearance and accumulation, is however unknown. Here, we explored the hypothesis that long-term synaptic potentiation (LTP), potentially able to minimize the effects of neuronal loss by providing extra excitation of denervated neurons, is the most relevant form of adaptive plasticity in stable MS patients, and it is disrupted in progressing MS patients. We found that LTP, explored by means of transcranial magnetic theta burst stimulation over the primary motor cortex, was still possible, and even favored, in stable relapsing-remitting (RR-MS) patients, whereas it was absent in individuals with primary progressive MS (PP-MS). We also provided evidence that platelet-derived growth factor (PDGF) plays a substantial role in favoring both LTP and brain reserve in MS patients, as this molecule: (1) was reduced in the CSF of PP-MS patients, (2) enhanced LTP emergence in hippocampal mouse brain slices, (3) was associated with more pronounced LTP in RR-MS patients, and (4) was associated with the clinical compensation of new brain lesion formation in RR-MS. Our results show that brain plasticity reserve, in the form of LTP, is crucial to contrast clinical deterioration in MS. Enhancing PDGF signaling might represent a valuable treatment option to maintain brain reserve and to attenuate the clinical consequences of neuronal damage in the progressive phases of MS and in other neurodegenerative disorders.

As we have said a few times
plasticity is how the CNS learns and adapts to change and how if makes new contacts
in the nervous circuitry. This study suggests that there may be some problems
associated with this particularly in progressive MSers. Long term potentiation
(LTP) is part of the process by which memories are formed. In this study there
is the suggestion in that in PPMS there are differences in the LTP potential
compared to RRMSers. And that this correlates with the amount of platelet
derived growth factor is a factor that can come from platelets and other cells and
is notable for the stimulation of growth of oligodendrocytes. Is this the effect that is important? However as it has many potential effects delivery into the
CNS many be most useful in order to limit unwanted side effects.

Highly significant clinical, epidemiological and pathogenetic similarities between multiple sclerosis (MS) and nasopharyngeal sinusitis has led to the hypothesis that MS is caused by the inadvertent incorporation of the lymphatic drainage of the nasopharynx into the extracellular fluid circulation of the CNS. It has been postulated that, in response to antigenic and toxic products generated by the mucosal nasopharygeal flora, the leptomeninges and CNS parenchyma acquire the characteristics of a persistently stimulated lymphoid organ. Using an extensive panel of bacterial antibodies, tissues from exceptionally early cases, identified and classified using multifactorial cluster analysis, were screened for bacterial antigens using immunohistological methods. Anti-staphylococcal antibodies detected antigen co-locating with IgG/C3d immune complexes in pre-demyelinating and in primary lesions. The distribution of the antigen in relation to the morphogenesis of early acute MS lesions is detailed. Evidence for the intrathecal processing of staphylococcal antigen was obtained using isoelectric focusing and antigen imprinting to identify antigen-specific oligoclonal bands. Employing a combination of isoelectric focusing, western blotting and mass spectrometric analysis, evidence for the intrathecal processing of staphylococcal β-haemolysin (sphingomyelinase) was obtained using CSF from MS cases. While a myelinolytic transportable toxin may be an important component in the pathogenesis of demyelination, in oligodendrocyte apoptosis, and in deviant immune responses within the CNS, the detection of other as yet unidentified staphylococcal-positive and negative oligoclonal bands points to the involvement of a cocktail of transportable antigens leaking in a similar manner into the CNS from the paranasal sinus mucosal tissues where these molecules are conserved by the resident flora to manipulate and subvert the normal processes of local and systemic immunity. Evidence for the access of other bacterial transportables to the CNS in MS should now be sought. The presence of ‘high-output’ toxigenic bacterial strains within the nasopharyngeal flora of MS patients should also be explored. The use of tracer molecules to detect and quantify nose-to-brain transport in MS patients is clearly apposite.

Whilst it has been suggested that I had to wake up to new ideas of MS and reported on the bacterial toxin up the nasal superhighway hypothesis and suggested as ever that armchair scientists need to put meat on their stories, it has been pointed out that I may have been abit harsh and only half awake and missed this one.....which is hardly surprising because this rag called MSARDS, of which ProfG is an editor, is not on pubmed (for the forseeable future if I am not mistaken) so most people don't know the work exists. Maybe they (MSARDS) need to start putting their old articles out open source....yes go "green" especially as the first year was free to registered readers anyway to limit the strangle hold pubmed appears to be aiming Elsevier's (Publishing house of MSARDS) way. It would help their (MSARDS) impact factor as people would read then cite the work and this will then stimulate more submissions, which will help subscriptions...surely a win win

Anyway I digress and back to this paper this paper suggests that bacterial toxins moving up the nose are a trigger for MS. So rather than the Charcot project for Viruses it should be anti-biotics, so maybe the armchair scientist needs to do a proper trial and put someones money where their mouth is.

BACKGROUND/OBJECTIVE:Dalfampridine is the extended-release formulation of 4-aminopyridine and is approved for the symptomatic treatment of impaired mobility in patients with multiple sclerosis. Our aim was to examine the short- and long-term effects of treatment with dalfampridine on motoric and cognitive assessment parameters of multiple sclerosis (MS) patients over 9-12months.

METHODS:Fifty-two patients with MS with an EDSS between 4.0 and 7.0 and impaired mobility were evaluated for parameters of walking ability, MSFC, cognitive and motor fatigue and evoked potentials at treatment initiation with dalfampridine as well as 2weeks and after 9-12months later.

RESULTS:Thirty out of fifty-two patients (~60%) were still on treatment after 9-12months. Two weeks after treatment initiation, significant ameliorations could be found for T25FW, maximum walking distance as well as motoric and cognitive fatigue which still persisted after 9-12months. In contrast significant effects for velocity were observed only after 2 weeks, for improvement in PASAT only after 9-12months. A tendency for improvement of somatosensory evoked potentials was found in a subset of patients.

CONCLUSION: Dalfampridine shows positive short- and long-term effects on motoric and cognitive assessment parameters in an open-label observational study in a cohort of patients with MS.

Fampridine can have long term benefits on walking outcomes. What's your experience.

Sunday, 22 December 2013

"The study below confirms my clinical observations that risk perception is affected by many factors and differs form one MSer to the next, and over time. MSers with early relatively inactive disease have a different PML risk threshold than those with highly-active or rapidly-evolving severe MS. The latter is understandable; if you have very active disease and are now doing well on natalizumab with no relapses and little disability would you want to take the risk of rebound on withdrawal, or move to a potentially less effective therapy? Your experience of having bad MS that is now under control is your counterbalance of the risk of possibly developing PM in the future. I also have several MSers under my care who are so risk adverse that they would rather take their chances with MS; it may be a coincidence but this latter group of MSers are often religious. In other words The course of their life is predetermined and whatever modern medicine has to offer this will not change their destiny."

"Despite MSers early in their course of disease - who typically have inactive disease and no disability - being generally relatively risk adverse there is a significant minority of MSers who soon after diagnosis are prepared to take huge risks to treat, and hopefully suppress or cure, their disease. These MSers tend to self-aware individuals who have done a lot of research about MS via the web and are acutely aware of the prognosis of MS if left to its own devices. These are the MSers who want to be treated with alemtuzumab or bone marrow transplantation as soon as possible. I find it difficult talking these people out of this situation, which I am forced to do, knowing full well that if I had been diagnosed with MS I would want to go this route. The reality in the UK is that early induction therapies are simply not available under the NHS to treat MS. Maybe NICE will recapitulate and allow us to use alemtuzumab and more importantly to use it first-line?"

"Risk is a large subject and needs more time; when I get a moment in the future I will post something from the psychology literature on this topic. It is very interesting in that personality and gender play a role in risk perception. What I do know is that in general neurologists are more risk adverse than MSers and this may be half the problem we are having in getting the field to move toward early highly-effective treatments and the paradigm of treating-2-target of NEDA."

OBJECTIVE: We aimed to investigate the ability of natalizumab (NTZ)-treated MSers to assume treatment-associated risks and the factors involved in such risk acceptance.

METHODS: From a total of 185 MSers, 114 MSers on NTZ as of July 2011 carried out a comprehensive survey. We obtained disease severity perception scores, personality traits' scores, and risk-acceptance scores (RAS) so that higher RAS indicated higher risk acceptance. We recorded JC virus status (JCV+/-), prior immunosuppression, NTZ treatment duration, and clinical characteristics. NTZ MSers were split into subgroups (A-E), depending on their individual PML risk. Some 22 MSers on first-line drugs (DMD) acted as controls.

RESULTS: No differences between treatment groups were observed in disease severity perception and personality traits. RAS were higher in NTZ than in DMD patients (p<0.01). Perception of the own disease as a more severe condition tended to predict higher RAS (p=0.07). Higher neuroticism scores predicted higher RAS in the NTZ group as a whole (p=0.04), and in high PML-risk subgroups (A-B) (p=0.02). In low PML-risk subgroups (C-E), higher RAS were associated with a JCV+ status (p=0.01). Neither disability scores nor pre-treatment relapse rate predicted RAS in either group.

CONCLUSIONS: Risk acceptance is a multifactorial phenomenon, which might be partly explained by an adaptive process, in light of the higher risk acceptance amongst NTZ-treated MSers and, especially, amongst those who are JCV seropositive but still have low PML risk, but which seems also intimately related to personality traits.

Background: The extended disability severity scale (EDSS) is clinically useful in assessing disability in multiple sclerosis (MS) patients. It is also being used in studies to determine how genes and environment influence disability. However, since it has a complex relationship with functional scores and mobility and is strongly determined by disease duration its use can be limiting.

Objective: Study associations of variables with progression described by time from disease onset until EDSS.

Methods: We used a variable based on below/above median time from MS onset to reach a single EDSS value to define slow or fast progression. We compared patient categorization using this variable and MSSS, and in 533 patients (EDSS 1–8) and 242 of these patients with EDSS1–4, studied associations with skin type, gender, ultraviolet radiation.

Results: Classifying patients into quartiles of slow/fast progression showed mean MSSS increased with faster progression (p<0.001). For EDSS 1–8: MSSS, late onset age and childhood sunburning were associated with fast progression. Combinations of skin type (1/2 or 3/4) with childhood weekend exposure (< or ≥median) or sunburning (yes/no) were not associated with progression. However, in patients with EDSS1–4, relative to other combinations, those with no sunburning history and types 1/2 demonstrated slow progression (odds ratio=0.15, 95% CI=0.04, 0.57).

Conclusion: This method, though a pilot, allows study of associations of variables with EDSS. It is based on local patients and could substitute for MSSS. In patients with EDSS1–4 but not 1–8, skin type 1/2 with no history of childhood sunburning was associated with slow progression. This is compatible with the view that disability develops through a first stage dependent on inflammation.

OBJECTIVES:To evaluate the concept that iron depletion (ID) induced by bloodletting and followed by recombinant human erythropoietin (rhEPO) administration could be a therapeutic strategy in progressive multiple sclerosis (PMS) and that it could be assessed by neurophysiological measurements.

PATIENTS AND METHODS:In four patients with PMS, bloodletting was performed until ID was induced, and then rhEPO was administered (300UI/kg/week). The changes induced by the treatment were assessed by clinical scores, biological tests, and neurophysiological study of cortical excitability using transcranial magnetic stimulation techniques.

RESULTS:The treatment was well tolerated except for muscle cramps and one popliteal vein thrombosis in a patient confined to chair. ID was obtained within 28 weeks and was associated with endogenous production of EPO. No bloodletting was further required during a six-month period after introduction of rhEPO. At the end of the follow-up (up to one year), fatigue and walking capacities tended to improve in two patients. Neurophysiological changes were characterized by an increased cortical excitability, including a decrease of motor thresholds and an enhancement of intracortical facilitation and cerebellothalamocortical inhibition.

CONCLUSIONS:The combined ID-rhEPO therapy could authorize a prolonged administration of rhEPO in PMS patients, able to modify cortical excitability of the glutamatergic and gabaergic circuits. These preliminary data are encouraging to design a larger, controlled therapeutical trial to assess the value of such a strategy to improve functional symptoms in PMS patients, and maybe to prevent axonal degeneration. Neurophysiological measurements based on cortical excitability studies could provide sensitive parameters to evaluate treatment-induced changes in this context.

It is accepted that there is iron accumulation in MS lesions. Iron is found in haemoglobin in red blood cells and EPO can increase the production of cells, which helps athletes get more oxygen and get better performance. This is why cyclists used it to cheat, e.g Lance Armstrong. This study bled people with MS and then gave them EPO. Erythropoietin, independent of the haematopoietic effects can promote neuroprotective effects. I am afraid n=4 tells us nothing and this is not enough evidence to suggest do nothing.

Saturday, 21 December 2013

"Wow, what an interesting case. It shows that MSers are not immune to other neurological disorders including neurotoxins. In fact MSers are more likely to suffer the ill effects of neurotoxins; MS reduces brain reserve therefore MSers are more susceptible to any drug, toxin or process that affects brain function. This includes side effects of drugs, head injuries or other age-related diseases for example stroke of Alzheimer's disease. The MSer described below was not doing well on natalizumab and was found to be ingesting a neurotoxin; a very unusual neurotoxin at that."

"I was taught at medical school to always take a step backwards and ask the question can it be anything else? In this case it was; it was not MS but a toxin. A clue was encephalopathy; this refers to a clinical syndrome characterized by clouding of consciousness. The latter is very rarely due to MS."

IMPORTANCE: Environmental factors are thought to be critical in the initiation and perpetuation of multiple sclerosis disease activity.

OBSERVATIONS: We describe the case of a woman in her late 30s with a diagnosis of relapsing-remitting multiple sclerosis, who continued to accumulate neurological disability despite long-term natalizumab treatment. The patient continued to have visual symptoms, left leg weakness, and gait instability. In addition, she subacutely developed an encephalopathy. Our investigations revealed that the patient had a long-standing history of chewing on toilet bowl deodorizing cakes. The main ingredient in this product is 99.9% paradichlorobenzene, which is also used in mothballs.

CONCLUSIONS AND RELEVANCE: This case illustrates that environmental causes for neurological deterioration should be investigated in MSers who display a rapidly progressive disease course and in whom potent pharmacotherapies fail. One possible cause is the ingestion of paradichlorobenzene-containing mothballs and toilet cleaners.

BACKGROUND:Smoking may contribute to the induction of neutralizing antibodies to interferon β-1a.OBJECTIVE:In this study, we aimed to investigate the influence of smoking on the risk of developing antibodies to natalizumab, another biological drug in the treatment of multiple sclerosis.METHODS: This report is based on 1338 natalizumab-treated multiple sclerosis patients included in either of two Swedish case-control studies in which information on smoking habits was collected. Using logistic regression, patients with different smoking habits were compared regarding risk of developing anti-natalizumab antibodies, by calculating odds ratios with 95% confidence intervals.RESULTS: Compared with nonsmokers, the odds ratio of developing anti-natalizumab antibodies was 2.4 (95% CI 1.2-4.4) for patients who smoked at the time of screening, and a significant trend showed higher risk of developing antibodies with higher intensity of smoking. When smoking within two years prior to screening was considered, the odds ratio of developing anti-natalizumab antibodies was 2.7 (1.5-5.1).INTERPRETATIONS:The finding strengthens our hypothesis of the lungs as immune-reactive organs on irritation in relation to autoimmune responses, and may also be of clinical relevance since antibodies against natalizumab abrogate the therapeutic effect of the treatment.

Yet more anti-smoking news. This study suggests that smokers are twice as likely to develop neutralising antibodies, which will stop the treatment working, as non-smokers. Now it is suggested that smoking affects MS risk and other aspects. Is this telling us that B cells are more important than T cells when it comes to MS. This study implies the reason is that cells that traffic into the CNS go to the lung first so the smoke filled lungs influence immunity. This idea was based on cell trafficking studies, where it is clear the lungs act as a filter for most of the injected cells There are other studies, which do not support this view of trafficking and the first question is why would they need to do this, it seems overly complicated?

Friday, 20 December 2013

Is rebranding MS a dementia stigmatizing? #MSBlog #MSResearch #ClinicSpeak"The following meta-analysis shows that we have not found a treatment to for MS-related cognitive impairment. Are you surprised? I am not. The assumptions that drugs that work in Alzheimer's disease will work in MS is simply wrong. The substrate of cognitive impairment in MS is likely to be very different to Alzheimer's disease. Alzheimer's cause a selective loss of neurones in specific areas of the brain and the type of cognitive impairment in Alzheimer's is different to that what we see in MS. "I have been lobbying Pharma, who are best at drug discovery, to focus on the issue of MS-related cognitive impairment; the unmet need is massive and having something that improves cognitive impairment in MSers will have a big impact on the quality of life of MSers. Fatigue, in particular mental fatigue, is driven by cognitive impairment. MSers adapt to cognitive impairment by using their reserve to complete cognitive tasks. The mental effort in doing this is exhausting and leaves MSers very tired. I am sure that this is the main driver of early unemployment in MS. In Europe 50% of MSers are unemployed within 10 years of diagnosis when they are unlikely to be physically disabled (EDSS <= 3.5); why? Cognitive impairment, fatigue and mood all play a part in early unemployment rates, not to mention social stigma. This is why a treatment for MS-related cognitive impairment is so important. The other issue is premature ageing; we all rely on cognitive reserve to fight off the ravages of ageing. MSers who have lost their cognitive reserve will be less able to adapt to ageing. This is why I am actively promoting early effective treatment to protect and save as much brain as possible so MSers can age well. Prevention is better than cure hence early effective treatment with DMTs that delay or slow brain atrophy are a "no brainer" to me. What do you think?""I did launch a campaign earlier this year to rebrand MS a dementia, but got slapped down by MSers and my peers. They think term dementia is too stigmatizing. What do yo think? The issue is if we don't focus on this issue we won't get regulators and payers to shift the paradigm to early highly-effective treatments."

"For those of you with cognitive impairment you may be interested in the MS Trust's staying smart programme. A few MSers I look after who tried the programme have said that it helps them."
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BACKGROUND: This is an update of the Cochrane review "Pharmacologic treatment for memory disorder in multiple sclerosis" (first published in The Cochrane Library 2011, Issue 10). MS is a chronic immune-mediated, inflammatory, demyelinating, neurodegenerative disorder of the central nervous system (CNS) and can cause both neurological and neuropsychological disability. Both demyelination and axonal and neuronal loss are believed to contribute to MS-related cognitive impairment. Memory disorder is one of the most frequent cognitive dysfunctions and presents a considerable burden to MSers and to society due to the negative impact on function. A number of pharmacological agents have been evaluated in many existing randomised controlled trials for their efficacy on memory disorder in MSers but the results were not consistent.OBJECTIVES: To assess the absolute and comparative efficacy, tolerability and safety of pharmacological treatments for memory disorder in adults MSers.SEARCH METHODS: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the Central Nervous System Group Trials Register (24 July 2013), PsycINFO (January 1980 to 26 June 2013) and CBMdisc (1978 to 24 June 2013), and checked reference lists of identified articles, searched some relevant journals manually, registers of clinical trials and published abstracts of conference proceedings.SELECTION CRITERIA: All double-blind, randomised controlled parallel trials on pharmacological treatment versus placebo or one or more pharmacological treatments in adults MSers who had at least mild memory impairment (at 0.5 standard deviations below age- and sex-based normative data on a validated memory scale). We placed no restrictions regarding dose, route of administration and frequency; however, we only included trials with an administration duration of 12 weeks or greater.DATA COLLECTION AND ANALYSIS: Two review authors independently assessed trial quality and extracted data. We discussed disagreements and resolved them by consensus among review authors. We contacted principal investigators of included studies for additional data or confirmation.MAIN RESULTS: We included seven randomised controlled trials (RCTs) involving 625 MSers mostly with relapsing-remitting, secondary-progressive and primary-progressive MS, evaluating the absolute efficacy of donepezil, ginkgo biloba, memantine and rivastigmine versus placebo in improving memory performance with diverse assessment scales. Overall, clinical and methodological heterogeneities existed across these studies. Moreover, most of them had methodological limitations on non-specific selections of targeted sample, non-matched variables at baseline or incomplete outcome data (high attrition bias). Only the two studies on donepezil had clinical and methodological homogeneity and relatively low risks for bias. One RCT evaluating estriol versus placebo is currently ongoing.We could not carry out a meta-analysis due to the heterogeneities across studies and the high attrition bias. A subgroup analysis for donepezil versus placebo showed no treatment effects on total recall on the Selective Reminding Test (mean difference (MD) 1.68; 95% confidence interval (CI) -2.21 to 5.58), total correct scores on the 10/36 Spatial Recall Test (MD -0.93; 95% CI -3.18 to 1.32), the Symbol Digit Modalities Test (MD -1.27; 95% CI -3.15 to 0.61) and the Paced Auditory Serial Addition Test (2+3 sec) (MD 2.23; 95% CI -1.87 to 6.33). Concerning safety, the main adverse events were: diarrhoea (risk ratio (RR) 3.88; 95% CI 1.66 to 9.05), nausea (RR 1.71; 95% CI 0.93 to 3.18) and abnormal dreams (RR 2.91; 95% CI 1.38 to 6.14). However, the results in both studies were subjected to a serious imprecision resulting from the small sample sizes and the low power of test (lower than 80%), which contributed to a moderate quality of the evidence. No serious adverse events were attributed to the treatments in all experimental groups.AUTHORS' CONCLUSIONS: We found no convincing evidence to support the efficacy of pharmacological symptomatic treatment for MS-associated memory disorder because most of available RCTs had a limited quality. Whether pharmacological treatment is effective for memory disorder in MSers remains inconclusive. However, there is moderate-quality evidence that donepezil 10 mg daily was not effective in improving memory in MSers with mild memory impairment, but had a good tolerability. Adverse events such as nausea, diarrhoea and abnormal dreams were not frequent but were associated with treatment. Ginkgo biloba, memantine and rivastigmine were safe and well tolerated and no serious adverse effects were reported. Future large-scale RCTs with higher methodological quality are needed.

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